MHC and Antigen Presentation

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The Major Histocompatibility Complex

a set of closely linked genetic loci (genes of the MHC) that have been found to be overwhelmingly important in determining the ate of engrafted tissue. This set of linked loci is highly polymorphic and plays a central role in control of the cellular interactions responsible for physiological immune responsiveness. There are two main types of MHC gene products (Class I and Class II molecules) and their physiological function is to present peptides to T lymphocytes.

Class I Loci

present on virtually all nucleated cells. present antigen to CD8+ T lymphocytes. HLA-A, HLA-B, HLA-C. (HLA = human leukocyte antigens)

Class II Loci

found on dendritic cells, B-lymphocytes, and macrophages. present antigen to CD4+ lymphocytes. HLA-D Subset : (DR, DQ, DP)

Class I Loci Molecules (A, B, C of humans)

each of the loci codes for a polypeptide chain of about 44,000 daltons. on cell membranes these chains as associated non-covalently with a lighter chain beta2 microglubulin, which is specified by a gene on another chromosome. the resulting cell surface molecule has one alpha chain, the class I polypeptide, and one light chain, beta2 microglobulin. MHC class I molecules bind short peptides of about 9 amino acids. remember these are presenting to CD8+ T lymphocytes.

Class II Loci Molecules (D of humans)

each of the loci codes for a polypeptide chain of about 60,000 daltons with two polypeptide chains per molecule. alpha and beta chains. (so this one is a little bigger than class I and not associated with any little beta2 microglobulin.) MHC class II molecules bind longer peptides of 13-17 amino acids in longer. sometimes the peptide flops out. remember these are presenting to CD8+ lymphocytes.

anchor residues

the residues on a peptide which interact directly with the MHC class molecule. they don't have to identical but are always related.

Co-dominant expression of MHC Antigens

Each individual expresses in a co-dominant fashion the class I and class II genes of both chroosomes 6. So each individual expresses 3 maternal and 3 paternal class Is (A, B, C), and 3 maternal and 3 paternal class IIs (DP, DQ, DR). Each individual has two "half sets" (haplotypes) of genes, one from each parent. both of these haplotypes are expressed equally.

are there many alleles for each MHC gene?

yes, with the possible exception of the DR alpha locus. the differences are all in the peptide-binding groove. it is a highly polymorphic, many different alleles situation, and each one of those can present more than one peptide (remember anchor residues) hundreds of different versions of alleles of the MHC in the human population as a whole but each individual carries only a small selection of them.

Cellular Interactions and MHC

a specific T cell response to antigen (Ag) on cell surface depends not on recognition of the Ag alone but on recognition of an antigenic peptide in the groove of an MHC molecule on the cell surface.

CD8+ T cells

cytolytic. Class I MHC

CD4+ T cells

helper. Class II MHC

MHC Restriction

a given T cell is restricted to recognize a peptide antigen only when it is bound to self-MHC molecules(lymphocytes typically interact with foreign antigen recognized by the lymphocyte in the context of host(self)-MHC molecules.) the fact that a T cell receptor recognizes a particular foreign peptide in the context of a particular MHC molecule.

What do cytotoxic (CD8+) T cells react with?

viral peptides in the context of the host cells class I MHC.

APCs

Macrophages, Dendritic Cells, and B Lymphocytes. antigen presenting cells, by profession. so these are class II MHC molecules, even though all nucleated cells express MHC class I molecules and can present antigen via these molecules.

plasmacytoid dendritic cells

plasmacytoid dendritic cells produce large quantities of interferon in response to viral infections.

conventional Dendritic Cells

undergo a maturation process as they move from highly phagocytic immature DC to mature DC that present large quantities of peptide in the context of MHC class II.

MHC class II Antigen Processing

antigens have been captured and internalized, and are then degraded enzymatically in endosomes and lysosomes, into peptides that bind MHC class II molecules. the class II MHC molecules are synthesized in the endoplasmic reticulum and are transported (with a little Ii chain in the peptide groove) to the endosomes to meet the peptide. The Ii is the cleaved to CLIP, then CLIP is removed by an unloadeder/loader (DM), which then puts the antigen peptide in there. then the whole complex transits to the cell surface.

MHC Class I Antigen Processing

these antigenic peptides are typically derived from viruses that have infected and hijacked the cells machinery. the peptides are generated in the cytoplasm, degraded by proteosomes, transported to the endoplasmic reticulum (via TAP-1 and TAP-2), assemmbled with MHC I the help of chaperones, released from the TAP complex, and exported to the cell membrane.

Do CD4+T lymphocytes recognize free or soluble antigens?

no, they only recognize antigen on the surface of the APCs in the context of class II molecules.

What is the subset of CD4+ T cell lymphocyte that activates macrophages?

Th1

What is the subset of CD4+ lymphocyte that induce antibody synthesis?

Th2

What are the major differences between a immature or naive DC and a mature DC?

immature DC are highly phagocytic but do not present antigen particularly well. after they nom something, then they mature and present antigen very well to T lymphocytes. maature DCs also express co-stimulatory molecules or cytokines

what do mature DC cells express on their cell sufaces?

large amounts of co-stimulatory molecules, eg. B7 (aka CD80 and CD86), and can also produce large quantities of cytokines required for T lymphocyte proliferation and differentiation.

how does a naive T cell get activated by antigen with APC that express B7?

requires 2 signals. first signal is the presentation of peptides by MHC and the second signal is the interaction between B7 on the APC and CD28 on the membrane of the T cell.

how does a T cell get activated by antigen with an APC that does not express B7?

T cells that recognize MHC II-peptides also have CD40L. This CD40L engages CD 40 on the surface of the APC and this signal induces the expression of B7 by the APC.

T Cell Mediated B-Cell activation

requires 2 signals. B cells take up antigen, then B cells process antigen and display processed peptides on MHC class II molecules. This process activates the B cell to make B7. T cells recognize MHC presented antigen and B7 co-stimulates CD28 on the surface of the T cell to activate the naive T cell. This activation induces the expression of CD40L. CD40L engages CD40 on the surface of the B cell, activating the T cell to produce cytokines, allowing the B cell to proliferate and differentiate into plasma cells that secrete antibody.

Immune Synapse

the interface between an APC and a lymphocyte. TCR engagment.

What do TCR (t cell antigen receptors) ligand to in the immune synapse?

MHC-peptide complexes

What does CD 28 ligand to in the immune synapse?

B7

What does CD 40 ligand to in the immune synapse

CD40L

How long does it take to trigger an effector function from an immune synapse?

It depends. Killer T cell execution may take hardly any time at all, whereas T cell proliferation and more complex stuff like it may take many minutes or hours.

what can surround the central cluster of TCRs in an immune synapse?

coencentric rings of adhesion molecules, such as LFA-1, ICAM-1 etc.

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